Cancer is a complex pathology manifested by uncontroIled growth of cells that have undergone various transformations from physiologically normal cells. Several hallmarks provide a methodical and rational approach in studying this disease, namely the sustaining of proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, activation of invasion, and metastasis [1]. In recent years, however, strong evidence has highlighted the important role of immune cells present in the tumor micro-environment [2, 3]. For instance, one way that tumor cells can modulate and escape immune destruction is by secretion of various factors such as pro-inflammatory eicosanoids, cytokines, chemokines and other soluble signaling molecules leading to the formation of an immunosuppressive tumor micro-environment [4].
Galectins are multifunctional proteins belonging to the animal lectin family. All galectins share similar binding affinities to β-galactosides and display high amino acid sequence homology among their carbohydrate-binding domains (CRDs) [5]. In mammals, 19 different members have been identified, and 13 of them have been identified in humans. Galectins are divided in three sub-groups according to their structure: prototypic galectins containing one CRD (Gal-1, -2, -5, -7, -10, -13, -14, -15, -16, -17, -19, and -20), tandem-repeat galectins containing two-CRDs covalently linked (Gal-4, -6, -8, -9 and -12) and a chimera-type galectin containing multiple CRDs linked by their amino-terminal domain (Gal-3) [6, 52, 53]. While these proteins perform homeostatic functions inside normal cells, under pathological or stress conditions, cytosolic galectins are released either passively from dead cells or actively via non-classical secretion pathways [7]. Once in the extracellular milieu, they bind all glycosylated growth receptors on the surface of normal and cancer cells to set their signaling threshold [8, 9]. Such properties enable galectins to kill infiltrating immune cells while promoting growth of tumour cells [9]. Galectins are thus ideal targets for effective therapeutics, and new approaches are therefore being developed to modulate their activities [10]. These avenues have focused mainly on carbohydrate-based inhibitors disrupting extracellular galectins, which form multivalent complexes with cell surface glycoconjugates to deliver CRD-dependent intracellular signals that modulate cell activation and survival/apoptosis. Despite decades of research, however, the progression in this field has been very slow. In most cases, these inhibitors are high molecular weight, naturally occurring polysaccharides that are used to specifically block the binding of extracellular galectins to carbohydrate structures [11-14]. Unfortunately, such inhibitors often display low affinity, lack of selectivity for a given galectin due to highly conserved homology among galectin CRDs, and are not effective at targeting CRD-independent functions of galectins. Indeed, several studies have shown that several critical biological processes of galectins are mediated via CRD-independent interactions [15-18].
There is thus a need for novel modulators of galectins, for example inhibitors that targets CRD-independent functions of galectins.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.